The discovery of HIV, the etiological agent for AIDS , led to the identification of a number of biochemical targetstocombatthisdevastatingdisease.Amongthem,therapeuticinhibitionofaproteolyticenzyme,HIV- 1 protease, emerged as a critical drug-development target. Subsequent design and discovery of protease inhibitors (Pis) and their introduction into the highly active antiretroviral therapy (HAART) , marked the beginning of a new era of management of HIV-1 infection and AIDS. HAART significantly improved the quality of life and life expectancy of patients. There is no cure for HIV/AIDS and long-term treatment has posed a serious challenge because of the emergence of multidrug-resistant HIV-1 variants. The majority of patients who initially achieved favorable viral suppression to undetectable levels experienced treatment failure. These drug-resistant HIV strains can be transmitted, raising further uncertainty with respect to future treatment options. In addition, Pis are faced with a number of serious limitations including, major toxicity, tolerance, and adherence to complex medical regimens. Our collaborative research efforts to combat drug resistance, led to the development of darunavir which was first approved for treatment against drug-resistant HIV in June, 2006, and then received full approval for all HIV/AIDS patients including pediatric patients in December, 2008. While darunavir has become a front line therapy against HIV/AIDS, it is far from ideal as a long-term treatment option . During this project period, based upon X-ray crystal structures of complexes of darunavir or other Pis with HIV-1 protease, we designed and synthesized a diverse class of potent Pis with marked antiviral activity, and excellent drug-resistance profiles against multidrug-resistant HIV-1 strains. We have also developed tools and important 'backbone binding' design concepts to combat drug-resistance. In our ongoing research, we have integrated our expertise in structure-based design and synthesis with strong talents in protein-ligand X-ray crystallography and in-depth virus and cell biological studies and created a number of exceptionally potent nonpeptide HIV-1 protease inhibitors with clinical potential.